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At least 1,243 records · Page 69Linked to original sources
PubMed1998

Despite its homology to angiostatin apolipoprotein(a) does not affect angiogenesis.

Apolipoprotein(a) [apo(a)] contains a kringle domain(IV) homologous to that of angiostatin, a natural angiogenic inhibitor. Because of this structural similarity we suspected that apo(a) could be an inhibitor of angiogenesis. The possible role of apo(a) in microvascular proliferation was studied in an in vivo quantitative model, the disc angiogenesis system (DAS) and compared to angiostatin. Apo(a) and other test compounds were placed in the center of a polyvinyl alcohol foam disc that was implanted subcutaneously in mice. After 14 days, the disc was removed and vascular growth into the disc was measured. Apo(a) did not affect spontaneous vessel growth into the disc, while angiostatin suppressed this growth and basic fibroblast growth factor (bFGF) increased it. Additionally, apo(a) did not modify the vascular growth induced by bFGF. Transgenic mice expressing the human apo(a) gene were used to study the systemic effect of apo(a): neither an increase nor a decrease in vascular growth was detected. Our results suggest that apo(a) is unlikely to play a significant role in the control of angiogenesis. Furthermore, our experiments confirm the inhibitory effect of angiostatin not only on induced angiogenesis but also on baseline, spontaneous angiogenesis.

Angiostatins↗
PubMed1994

Beware of using small statistical samples when assessing the quality of a DNA library.

DNA libraries often contain very large numbers of clones (from 1000 up to 700,000). Since at present it is impossible to analyze all of these clones, usually statistical samples comprising less than 100 clones are tested. The quality of the library is then assessed by linear extrapolation. Occasionally, full coverage of chromosomal regions by DNA probes is inferred from this. However, this may not be accurate since linear extrapolation is misleading and the statistical samples are generally too small to characterize the libraries. A quantitative model of the distribution of the frequencies of the clones in a library is mandatory for any useful assessment of the quality of the library. Otherwise, it is very difficult to draw useful conclusions from moderately sized samples. Examples from everyday life and formulas are given to determine the quality of a library and useful sample sizes.

Chromosome Walking↗
PubMed2000

Rates of Mass Transfer and Adsorption of Hexadecyltrimethylammonium Bromide at an Expanding Air-Water Interface.

An overflowing cylinder (OFC) provides a convenient method for studying nonequilibrium liquid interfaces under steady-state conditions. In the presence of surfactants in solution, large accelerations in the surface velocity are observed as a result of Marangoni effects. The surface expansion rate is approximately uniform over the surface of the OFC and falls in the range of 1-10 s(-1). In this paper, a quantitative model is presented for the mass transport to the expanding surface of the OFC. The model is then used to analyze experimental measurements of surface expansion rates and surface excess for solutions of a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB), obtained by laser Doppler scattering and neutron reflection, respectively. The experimental results are in satisfactory agreement with the predictions of diffusion-controlled adsorption close to the critical micelle concentration (cmc). At concentrations well above and well below the cmc, kinetic barriers to adsorption appear to exist. The data at low concentrations are discussed in terms of a model for mass transport through the electrical double layer. At high concentrations, double-layer effects are negligible and steric barriers to adsorption are postulated. Copyright 2000 Academic Press.

Journal Article↗
PubMed1998

Experimental Results on the Centipede Game in Normal Form: An Investigation on Learning.

We analyze behavior of an experiment on the centipede game played in the reduced normal form. In this game two players decide simultaneously when to split a pie which increases over time. The subjects repeat this game 100 times against randomly chosen opponents. We compare several static models and quantitative learning models, among them a quantal response, model reinforcement models and fictitious play. Furthermore, we structure behavior from period to period according to a simple cognitive process, called learning direction theory. We show that there is a significant difference in behavior from period to period whether a player has decided to split the pie before or after the opponent. Copyright 1998 Academic Press.

Journal Article↗
PubMed2001

Mechanism of oxygen response in carbon-based sensors.

The mechanism of oxygen response in several newly synthesized oxygen-sensitive chars was studied with the use of EPR spectroscopy. The results suggest that the compounds contain two basic types of paramagnetic centers (PC). The change in oxygen concentration leads to a mutual and reversible transformation of PCs in chars, which is reflected in EPR parameters. The adsorbed molecular oxygen progressively disturbs the wave functions of the PCs and so breaks the Heisenberg exchange between them. At high oxygen concentration, the 2D dipole-dipole interaction between PCs at the surface comes into play and determines the EPR lineshape. A suggested model quantitatively describes the evolution of the basic EPR parameters of each PC as a function of oxygen concentration.

Carbon↗
PubMed1995

An investigation into the role of phenotypic plasticity in evolution.

Phenotypic plasticity can modify evolutionary pathways and accelerate the course of evolution. This was brought out in a quantitative model by Hinton & Nowlan (1987, Complex Systems 1, 497-502). The present work confirms and extends their results. We consider a population of genetically haploid individuals of fixed size. Genotypes are represented by one-dimensional arrays (strings) of genes. Each gene can be in one of three allelic states, designated 1, 0 and X. 1 and 0 stand for fixed states, that is for states with predetermined effects on the phenotype. X stands for a plastic state: the phenotypic effect of an X can be equivalent to that of a 1 or a 0, the actual choice being realized by a process of random coin-tossing. Our model, in contrast to that of Hinton and Nowlan, assumes a relatively smooth dependence of fitness on distance from a pre-assigned target genotype. From the fitness values, the number of individuals reaching reproductive maturity is determined. Reproduction involves random mating and a single recombinational event, with one of the two progeny genotypes becoming, in turn, a possible parental genotype for the next generation. We find that it is because of the special assumptions in the Hinton and Nowlan model that phenotypic plasticity invariably accelerates evolution. The relationship is not as straightforward with realistic fitness schemes. Instead, the general result is that plasticity, up to a certain optimal level, slows down the rate of evolutionary change but improves the level of adaptation finally reached.

Adaptation, Physiological↗
PubMed2001

A reliable and safe T cell repertoire based on low-affinity T cell receptors.

Antigens are presented to T cells as short peptides bound to MHC molecules on the surface of body cells. The binding between MHC/peptides and T cell receptors (TCRs) has a low affinity and is highly degenerate. Nevertheless, TCR-MHC/peptide recognition results in T cell activation of high specificity. Moreover, the immune system is able to mount a cellular response when only a small fraction of the MHC molecules on an antigen-presenting cell is occupied by foreign peptides, while autoimmunity remains relatively rare. We consider how to reconcile these seemingly contradictory facts using a quantitative model of TCR signalling and T cell activation. Taking into account the statistics of TCR recognition and antigen presentation, we show that thymic selection can produce a working T cell repertoire which will produce safe and effective responses, that is, recognizes foreign antigen presented at physiological levels while tolerating self. We introduce "activation curves" as a useful tool to study the repertoire's statistical activation properties.

Humans↗
PubMed2000

Adaptive evolution of larvae and life cycles.

The larval patterns of marine invertebrates pose intriguing questions for both evolutionary and developmental biologists. However, combined investigations have been rare. Quantitative models analyze the selective factors that drive evolutionary change in larval nutrition and timing of metamorphosis. Developmental studies describe the morphogenesis characterizing ancestral and derived larval patterns. Rigorous evolutionary analysis of the transition to derived modes of development is lacking and detailed developmental and ecological data are needed to test and refine theoretical models. A major challenge facing studies of life cycle evolution is the elucidation of the genetic structure and covariance of important developmental and larval traits.

Adaptation, Physiological↗
PubMed1977

Regulatory factors of acetaldehyde metabolism in isolated rat liver mitochondria.

The factors affecting acetaldehyde oxidation were studied by direct measurement of redox changes of NADH and cytochrome c in isolated rat liver mitochondria which contain the natural complement of mitochondrial substrates and co-factors, etc. Thus, this system affords a quantitative model for mitochondrial acetaldehyde metabolism simulating in vivo conditions. The activity of acetaldehyde dehydrogenase, as measured by the turnover number of cytochrome c, k3, depends upon the substrate concentration in a complex way. It reaches a maximum below 0.033 mM acetaldehyde and decreases abruptly at higher acetaldehyde concentration, interpreted here to be due to substrate inhibition. When mitochondria undergo hypotonic swelling, the maximal value of k3 is lowered by a factor of 15 and the substrate inhibition largely disappears. When mitochondria are stripped of the outer membrane and are suspended in pyrophosphate buffer, similar effects are obtained. It is concluded that acetaldehyde oxidation in mitochondria is dependent upon the state of mitochondria and the substrate concentration, and that the mitochondrial metabolism of acetaldehyde cannot be accurately predicted from in vitro data of solubilized enzyme.

Acetaldehyde↗
PubMed2007

Systems biology and its impact on anti-infective drug development.

Systems biology offers the potential for more effective selection of novel targets for anti-infective drugs. In contrast to conventional reductionist biology, a systems approach allows targets to be viewed in a wider context of the entire physiology of the cell, with the potential to identify key susceptible nodes and to predict synergistic effects of blocking multiple pathways. In addition to the holistic perspective provided by systems biology, the emphasis on quantitative analysis is likely to add further rigour to the process of target selection. Systems biology also offers the potential to incorporate different levels of information into the selection process. Consideration of data from microbial population biology may be important in the context of predicting future drug-resistance profiles associated with targeting a particular pathway, for example. This chapter provides an overview of major themes in the developing field of systems biology, summarising the core technologies and the strategies used to translate datasets into useful quantitative models capable of predicting complex biological behaviour.

Anti-Infective Agents↗
PubMedDate not supplied

The pattern and timing of lymphatic metastasis of the rat carcinoma LMC.

The distribution pattern and latency of lymphatic metastases naturally disseminated by the Leeds Mammary Carcinoma (LMC1) when transplanted subcutaneously in isogeneic Johns' Strain Wistar rats has been determined. After the curative local irradiation and excision of the primary tumour in 210 rats, 55 +/- 3 per cent developed either local (26 +/- 3 per cent), and/or regional (28 +/- 3 per cent) and/or distant (37 +/- 3 per cent) lymph node metastases. Analysis of their pattern of distribution suggests that metastasis to local (inguinal and lumbar) and distant (axillary and mediastinal) nodes results mainly from the radial dissemination, trapping and nodal proliferation of cells released by the primary tumour. Although direct metastasis to the para-aortic node may have occurred, in the main seeding of this site and thence to other, regional, i.e. iliac and/or adrenal nodes, resulted from the dissemination of tumour cells from the local nodes. The latency of metastases appearing at different sites after primary tumour ablation, although highly variable, was site dependent and for local, regional and distant nodes was 30 +/- 14, 48 +/- 16, 56 +/- 17 days respectively. In addition, the latency of metastases at regional and distant nodes was directly correlated with the latency of local metastases. The latency of adrenal and iliac metastases also correlated with para-aortic node metastasis, as did mediastinal with axillary lymph node metastasis. From the data, a semi-quantitative model of lymphatic metastasis has been developed for further evaluation and adjuvant chemotherapy testing.

Adrenal Glands↗
PubMed1982

Ketoconazole: a new imidazole antifungal agent has both prophylactic potential and therapeutic efficacy in keratomycosis of rabbits.

A highly reproducible quantitative model of fungal infection of the rabbit's corneal stromal was produced using multiple corneal microtrephination. Aspergillus flavus (K4/77), at a concentration of 10(6) spores per ml was systematically implanted into the trephine sites in the cornea, and the degree of corneal infection determined. By pre-inoculation and post-inoculation challenge of these cornea with 1% ketoconazole in arachis oil, the prophylactic potential and the therapeutic usefulness of ketoconazole was determined. Ketoconazole, acetyl-dichlorophenyl-imidazole, has a significant prophylactic potential in inhibiting the development of corneal stromal fungal lesions when it is administered to the cornea of New Zealand white male rabbits as a 1% solution in arachis oil for two consecutive times hourly for two hours before the inoculation of the rabbits cornea with an ocular pathogenic Aspergillus flavus. Ketoconazole also has a therapeutic effect in the reduction of well established A. flavus keratitis in rabbits. When administered as 1% solution in arachis oil for ten consecutive hours daily to well established A. flavus lesions of the cornea of New Zealand albino rabbits, ketoconazole took about sixteen days to cure all the corneal lesions. Finally, using a yeast nitrogen base liquid medium, the in vitro minimal inhibitory concentrations of ketoconazole to twenty-five various human ocular pathogenic fungal isolates were determined and used to recommend those fungi for which ketoconazole would be a good choice for therapy.

Animals↗
PubMed1990

The lateral spread of signal between bipolar cells of the tiger salamander retina.

When mapped with a small spot of light, the central receptive fields of bipolar cells in the salamander retina are much larger than the extent of bipolar cell dendrites. Furthermore responses of bipolar cells to distant spots of light are considerably delayed relative to proximal spots. Using quantitative modelling, electrical coupling between bipolar cells is examined and rejected as a sufficient explanation of the data. An active process appears to shape signal waveform as signals spread laterally in the bipolar cell layer. Chemical synaptic coupling between bipolar cells is considered and shown to be inconsistent with the data. It is suggested that local, transient negative feedback from amacrine cells is involved in shaping bipolar cell signals.

Animals↗
PubMed1991

Components of the dynamic response of mammalian muscle spindles that originate in the sensory terminals.

One component of the dynamic response of muscle spindles is characterized by a phase lead and frequency dependent sensitivity in response to sinusoidal stretches at frequencies around 1 Hz. Possible mechanisms producing this component, designated the "mid-frequency" dynamics, were investigated by testing the hypotheses that they arise from the mechanical behavior of the intrafusal muscle and alternatively from within the sensory terminals. Destruction of the myofibrillar structure of the intrafusal muscle fibers did not alter the mid-frequency dynamics, indicating that they do not arise from viscoelastic properties of the intrafusal muscle. An Arrhenius plot of the temperature dependence of the mid-frequency dynamics yielded an equivalent activation energy of 6.5 Kcal/M in the temperature range 23-42 degrees C and a 3-fold higher activation energy at lower temperatures. These observations are consistent with a dynamic process associated with a membrane-bound biochemical process. The addition of Ca++ and Ca(++)-activated-K+ (K(Ca] channel blockers (ZnCl2, Apamin and TEA) to the bathing solution altered the response dynamics by reducing the mid-frequency phase lead. The results suggest a negative feedback on the membrane potential generated by K+ efflux following a Ca++ influx that opens K(Ca) channels. A quantitative model fit to the experimental data yields a time constant of about 80 ms representing the limiting process associated with activation of the K(Ca) channels in this system. The results indicate that the mechanism underlying the mid-frequency dynamics includes at least two processes: one, not identified in this study, generates the phase lead and another, involving Ca++ and K(Ca) channels, provides a negative feedback that modifies the phase lead.

Animals↗
PubMed1994

Evidence for nonretinal feedback in combined version-vergence eye movements.

Recently, a quantitative model for the general of rapid eye movements in direction and depth was proposed. In this scheme, the saccadic and the vergence system share a common initiation system and are controlled by local feedback loops based on efference copy signals. We have used a remembered-target double-step paradigm to test the idea that both subsystems are guided by extraretinal signals. The subject was instructed to move the binocular point of fixation to the remembered positions indicated by a double-step movement of the target, in direction and depth. Since both binocular refixations were made in complete darkness, correct execution of this task requires information about both the stored visual coordinates of the final target and the coordinates of the first movement. Binocular eye movements from five subjects were compared with predictions from two feed-forward models and a feedback model. Analysis of the pooled direction data showed that the feedback model performed best and fitted well. Qualitatively the same result was obtained in the vergence component, but in this case the goodness of fit was considerably less. These results, confirmed in each individual subject, show that the saccadic and vergence subsystem can use nonretinal information about a prior movement in direction and depth. Further analysis showed that the gain of the direction response of the second movement was, on average, roughly correct. By contrast, the vergence component of these responses was only about 60% of the required amplitude. Since the fit procedure gave the same weighting factors to the second target and to the first movement, we propose that the low vergence gain reflects mechanisms operating after the calculation of the motor error signal, possibly at the execution stage. Finally, we discuss the possibility of a central control stage keeping track of the ongoing movement sequence, based on a comparison of desired and current eye position signals.

Adult↗
PubMedDate not supplied

Control of cardiac performance by Ca-turnover.

A quantitative model of Ca-turnover in cardiac cells that incorporates negative feedback modulation of sarcolemmal calcium transport (via Ca channels and Na/Ca exchange) has been designed. The Na/Ca exchange current was expressed as INaCa = INaCar + delta INaCa. The component INaCar reflects slow changes of Ca2+ and Na+ concentrations and depends on the Na/K pump. delta INaCa is the fast component related to the Ca2+ transient. The single input to the model is an arbitrary sequence of intervals between excitations; outputs are sequences of calcium amounts transferred among the compartments during individual intervals. The model operates with a combination of discrete variables (amounts of Ca transferred during contraction, relaxation and rest) and continuous variables - slow changes in ionic concentrations. Since the model is not formalistic but respects the nature of the underlying elements of the system, it enables us to stimulate the known effects of cardiotropic drugs or to predict their unknown mechanisms by visualizing the changes in individual Ca compartments. By altering the parameters, the model also stimulates the known species and tissue differences in rate-dependent phenomena.

Action Potentials↗
PubMed1981

Deconvolution analysis of 99mTc-methylene diphosphonate kinetics in metabolic bone disease.

The kinetics of 99mTc-methylene diphosphonate (MDP) and 47Ca were studied in three patients with osteoporosis, three patients with hyperparathyroidism, and two patients with osteomalacia. The activities of 99mTc-MDP were recorded in the lumbar spine, paravertebral soft tissues, and in venous blood samples for 1 h after injection. The results were submitted to deconvolution analysis to determine regional bone accumulation rates. 47Ca kinetics were analysed by a linear two-compartment model quantitating short-term mineral exchange, exchangeable bone calcium, and calcium accretion. The 99mTc-MDP accumulation rates were small in osteoporosis, greater in hyperparathyroidism, and greatest in osteomalacia. No correlations were obtained between 99mTc-MDP bone accumulation rates and the results of 47Ca kinetics. However, there was a significant relationship between the level of serum alkaline phosphatase and bone accumulation rates (R = 0.71, P less than 0.025). As a result deconvolution analysis of regional 99mTc-MDP kinetics in dynamic bone scans might be useful to quantitate osseous tracer accumulation in metabolic bone disease. The lack of correlation between the results of 99mTc-MDP kinetics and 47Ca kinetics might suggest a preferential binding of 99mTc-MDP to the organic matrix of the bone, as has been suggested by other authors on the basis of experimental and clinical investigations.

Adult↗
PubMed1995

Calcium tracer kinetics show decreased irreversible flow to bone in glucocorticoid treated patients.

Osteopenia resulting from pharmacologic doses of glucocorticoids is well known. Previously, there has been no satisfactory quantitative model describing the kinetics of calcium flow in subjects on chronic steroid use. A mathematical model of calcium isotope interaction with bone is described and applied to determine an estimate of kinetic parameters characterizing these changes. Calcium tracer dilution kinetics after a bolus injection of 42Ca were measured in 14 subjects with juvenile dermatomyositis, 6 on prednisone regimens and 8 on treatment regimens without prednisone. Irreversible tracer loss from plasma bone is found to be significantly reduced (P = 0.043) in the glucocorticoid-treated patients compared with patients on nonsteroid regimens. Reversible flow to bone is noted to be similar in the two groups. These results suggest a direct effect of glucocorticoids on osteoblast function.

Adolescent↗